Synthesis of celecoxib analogs that possess a N-hydroxypyrid-2(1H)one 5-lipoxygenase pharmacophore: biological evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity.
A hitherto unknown class of celecoxib analogs was designed for evaluation as dual inhibitors of the 5-lipoxygenase/cyclooxygenase-2 (5-LOX/COX-2) enzymes. These compounds possess a SO(2)Me (11a), or SO(2)NH(2) (11b) COX-2 pharmacophore at the para-position of the N(1)-phenyl ring in conjunction with a 5-LOX N-hydroxypyrid-2(1H)one iron-chelating moiety in place of the celecoxib C-5 tolyl group. The title compounds 11a-b are weak inhibitors of the COX-1 and COX-2 isozymes (IC(50)=7.5-13.2 microM range). In contrast, the SO(2)Me (11a, IC(50)=0.35 microM), and SO(2)NH(2) (11b, IC(50)=4.9 microM), compounds are potent inhibitors of the 5-LOX enzyme comparing favorably with the reference drug caffeic acid (5-LOX IC(50)=3.47 microM). The SO(2)Me (11a, ED(50)=66.9 mg/kg po), and SO(2)NH(2) (11b, ED(50)=99.8 mg/kg po) compounds exhibited excellent oral anti-inflammatory (AI) activities being more potent than the non-selective COX-1/COX-2 inhibitor drug aspirin (ED(50)=128.9 mg/kg po) and less potent than the selective COX-2 inhibitor celecoxib (ED(50)=10.8 mg/kg po). The N-hydroxypyridin-2(1H)one moiety constitutes a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of chelating 5-LOX iron for exploitation in the design of 5-LOX inhibitory AI drugs.
Chowdhury
Morshed Alam
MA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G 2N8.
Abdellatif
Khaled R A
KR
Dong
Ying
Y
Das
Dipankar
D
Suresh
Mavanur R
MR
Knaus
Edward E
EE
D000284:Administration, Oral; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002109:Caffeic Acids / Q000494:pharmacology; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004195:Disease Models, Animal; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005528:Foot / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002109:Caffeic Acids; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D011728:Pyridones; D013449:Sulfonamides; D000068579:Celecoxib; C040048:caffeic acid